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“Down Syndrome: an Insight of the Disease” Ambreen Asim, Ashok Kumar, Srinivasan Muthuswamy, Shalu Jain and Sarita Agarwal*

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“Down Syndrome: an Insight of the Disease” Ambreen Asim, Ashok Kumar, Srinivasan Muthuswamy, Shalu Jain and Sarita Agarwal* Asim et al. Journal of Biomedical Science (2015) 22:41 DOI 10.1186/s12929-015-0138-y REVIEW Open Access “Down syndrome: an insight of the disease” Ambreen Asim, Ashok Kumar, Srinivasan Muthuswamy, Shalu Jain and Sarita Agarwal* Abstract Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. DS is associated with number of phenotypes including congenital heart defects, leukemia, Alzeihmer’s disease, Hirschsprung disease etc. DS individuals are affected by these phenotypes to a variable extent thus understanding the cause of this variation is a key challenge. In the present review article, we emphasize an overview of DS, DS-associated phenotypes diagnosis and management of the disease. The genes or miRNA involved in Down syndrome associated Alzheimer’s disease, congenital heart defects (AVSD), leukemia including AMKL and ALL, hypertension and Hirschprung disease are discussed in this article. Moreover, we have also reviewed various prenatal diagnostic method from karyotyping to rapid molecular methods - MLPA, FISH, QF-PCR, PSQ, NGS and noninvasive prenatal diagnosis in detail. Introduction content of SINE’s, LINE’s, and LTR are 10.84%, 15.15%, Down syndrome is one of the most leading causes of in- 9.21% respectively. The Table 1 given below highlights tellectual disability and millions of these patients face some of the genes present on chromosome 21. various health issues including learning and memory, congenital heart diseases(CHD), Alzheimer’s diseases Features of DS (AD), leukemia, cancers and Hirschprung disease(HD). There are various conserved features occurring in all DS The incidence of trisomy is influenced by maternal age population, including learning disabilities, craniofacial ab- and differs in population (between 1 in 319 and 1 in normality and hypotonia in early infancy [13]. Some people 1000 live births) [1-5]. DS has high genetic complexity of DS are affected by variant phenotypes including atrio- and phenotype variability [6-8]. Trisomic fetuses are at ventricular septal defects (AVSD) in heart, leukemia’s(both elevated risk of miscarriages and DS people have in- acute megakaryoblastic leukemia(AMKL) and acute creased incidence of developing several medical condi- lymphoblastic leukemia(ALL)), AD and HD. DS individual tions [9]. Recent advancement in medical treatment with have variety of physical characteristics like a small chin, social support has increased the life expectancy for DS slanted eye, poor muscle tone, a flat nasal bridge, a single population. In developed countries, the average life span crease of the palm and a protuding due to small mouth for DS population is 55 years [10]. and large tongue [14]. Other features includes big toe, abnormal pattern of fingerprint and short fingers. Review Human Chromosome 21 Genetics of the disease DS complex phenotype results from dosage imbalance of The most common cause of having a DS babies is pres- genes located on human chromosome 21(Hsa 21). The ence extra copy chromosome 21 resulting in trisomy. genetic nature of DS together with the relatively small The other causes can be Robertsonian translocation and size of Hsa 21 encouraged scientist to concentrate efforts isochromosomal or ring chromosome. Ischromosome is towards the complete characterization of this chromo- a term used to describe a condition in which two long some in the past few years. The length of 21q is 33.5 Mb arms of chromosome separate together rather than the [11] and 21 p is 5–15 Mb [12]. A total 225 genes was es- long and short arm separating together during egg timated when initial sequence of 21q was published [11]. sperm development. Trisomy 21 (karyotype 47, XX, + 21 Hsa 21 has 40.06% repeat content out of which the repeat for females and 47, XY, + 21 for males) is caused by a failure of the chromosome 21 to separate during egg or * Correspondence: [email protected] Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of sperm development. In Robertsonian translocation Medical Sciences, Lucknow 226014, India which occurs only in 2-4% of the cases, the long arm of © 2015 Asim et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Asim et al. Journal of Biomedical Science (2015) 22:41 Page 2 of 9 Table 1 Some common gene present in chromosome 21 18]. The sequencing of Hsa 21 proved to be an import- S. no. Genes Abbreviation ant factor in the progression of DS research [19] and led 1. APP Amyloid beta (A4) precursor protein to further insight into genotype-phenotype correlations 2. C21 or f59: Chromosome 21 open reading frame 59 associated with DS and precise characterizations of DSCR regions [13]. A “critical region” within 21q22 was 3. CBS Cystathionine-beta-synthase believed to be responsible for several DS phenotypes 4. CLDN14 Claudin 14 including craniofacial abnormalities, congenital heart de- 5. HLCS Holocarboxylase synthetase (biotin-(proprionyl- fects of the endocardial cushions, clinodactyly of the coenzyme a-carboxylase (ATP-hydrolysing)) ligase) fifth finger and mental retardation [20]. 6. KCNE1 Potassium voltage-gated channel, Dual-specificity tyrosine phosphorylation-regulated kin- isk-related family, member 1 ase (DYRK1A) and regulator of calcineurin 1 (RCAN1), 7. KCNE 2 Potassium voltage-gated channel, Down syndrome cell adhesion molecule (DSCAM) has isk-related family, member 2 been suggested to play a critical role in the developing 8. LAD Leukocyte adhesion deficiency brain and has also been identified as a candidate gene for 9. SOD 1 Superoxide dismutase 1 the increased risk of CHD in DS individuals [21,22]. 10. TMPRSS3 Transmembrane protease, serine 3 DSCAM is a critical factor in neural differentiation, axon 11. PCNT Centrosomal pericentrin guidance, and the establishment of neural networks and it 12. DSCR1 Down Syndrome critical region 1 has been suggested that the disruption of these processes contributes to the DS neurocognitive phenotype [22]. 13. DYRK1A Dual specificity tyrosine-(Y)-phosphorylation regulated kinase 1A Based on thorough analyses of studies on humans and DS 14. RRPB1 Ribosomal RNA processing 1 homolog B mouse models, it is evident that there is not a single crit- ical region of genes sufficient to cause all DS phenotypes. 15. S100B Calcium binding protein Alternatively, it is likely that there are multiple critical re- gions or critical genes contributing to a respective pheno- type or group of phenotypes associated with DS [23]. the chromosome 21 is attached to another chromosome (generally chromosome 14). While mosaicism deals with Various clinical conditions associated to Down syndrome the error or misdivision occurs after fertilization at some The various clinical conditions associated with DS are point during cell division. Due to this people with mo- Alzheimer’s disease, heart defects, leukemia, hyperten- saic DS have two cell lineages which contribute to tis- sion and gastrointestinal problems (Figure 1). The mo- sues and organs of individuals with Mosacism (one with lecular pathogenesis mechanism of these DS related the normal number of chromosomes, and other one phenotype must be studied along with its causative with an extra number 21) [15]. agents in order to have a better understanding of the dis- ease. Below are some DS related phenotype discussed in Genotype-phenotype correlation detail which are as follows: Gene dosage imbalance hypothesis states that DS pa- tients have an increased dosage or copy number of genes Neurological problems on Hsa 21 that may lead to an increase in gene expres- DS patients have greatly increased risk of early onset AD. sion [13-15]. This hypothesis has been extended to in- After the age of 50, the risk of developing dementia in- clude the possibility that specific genes or subsets of creases in DS patients up to 70% [23-27]. There are vari- genes may control specific DS phenotypes [16]. Ampli- ous genes reported to cause early onset AD. Some of the fied developmental instability hypothesis states that a genes described in the current literature are APP (amyloid non-specific dosage of a number of trisomic genes leads precursor protein), BACE2 (beta secretase 2), PICALM to a genetic imbalance that causes a great impact on the (Phosphatidylinositol binding clathrin assembly protein) expression and regulation of many genes throughout the and APOE(Apolipoprotein E) etc. APP is an integral genome [13, 14]. Another hypothesis known as critical membrane protein which is concentrated in synapse of region hypothesis was also added to this list. Phenotypic neurons and trisomy of this protein is likely to make sig- analyses was done on individuals with partial trisomy for nificant contribution to the increased frequency of demen- Hsa21 identified that only one or a few small chromo- tia in DS individuals. The triplication of Hsa 21 along with somal regions, termed “Down syndrome critical regions” APP in people without DS has been recently shown to be (DSCR) a region of 3.8-6.5 Mb on 21q21.22, with ap- associated with early onset AD. A tetranucleotide repeat, proximately 30 genes responsible for the majority of DS ATTT , in intron 7 of the amyloid precursor protein has phenotypes [15,16]. Previously a region of 1.6 to 2.5 Mb been associated with the age of onset of AD in DS in a was recognised as sufficient cause for DS pehnotype [17, preliminary study [28]. Various mouse models are used to Asim et al. Journal of Biomedical Science (2015) 22:41 Page 3 of 9 observe degeneration of basal forebrain cholinergic neu- with complete AVSD suggests the defects in CRELD 1 rons (BFCNs).
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